Diagnostics and new treatment regimens for TB: can the Xpert MTB/XDR assay fill the gap for fluoroquinolone testing?

Abstract

Rapid diagnosis of resistance-conferring mutations to antibiotics used for the treatment of tuberculosis (TB) is critical for patient care and public health control efforts. Prior guidelines included the use of fluoroquinolones (FQs) for the treatment of drug-resistant TB, including multidrug-resistant TB, pre-extensively drug-resistant TB, and extensively drug-resistant TB. More recently, a short-course regimen for antibiotic-susceptible TB was introduced, which includes the use of a FQ, a drug class that diagnostic algorithms in the United States (US) typically do not test for if all first-line agents are susceptible. However, FQ mono-resistance has been documented by previous studies, and for this reason, we tested 319 archived Mycobacterium tuberculosis complex (MTBC) strains spanning a 14-year period of time using the Xpert MTB/XDR assay. Resistance to FQs was detected in 4.4% (14/319) of the isolates tested, with mutations predominating in the gyrA region (13/14; 92.9%). A single isolate (1/14; 7.1%) was found to have a gyrB mutation. A broth microdilution assay demonstrated the minimum inhibitory concentrations for resistant strains that ranged from 0.5 µg/mL to 8.0 µg/mL. Importantly, three strains were FQ mono-resistant and would have been completely missed by standard testing algorithms. Although currently unavailable in the US, the GeneXpert XDR assay has the potential to fill the significant diagnostic gap in susceptibility testing of MTBC resistance to FQs and support the use of the currently recommended short-course regimen.IMPORTANCE This study provides insight into the need for additional rapid testing for the detection of drug resistance (specifically to fluoroquinolones) in tuberculosis (TB) cases in the United States (US). The current regimens for TB treatment rely on knowing resistance patterns to optimize treatment, and missed resistance could have a negative impact on the health of the patient, as well as contribute to increased drug-resistance mutations in new TB cases. There are currently limited platforms for expanded rapid drug resistance testing for TB cases in the US, and this study looks at past TB cases that had drug resistance missed by routine testing.